- A study involving the IIBM identifies a protein that is key to the proper formation of the placenta and the area where nutrients and oxygen are exchanged between mother and fetus
- The absence of this protein reduces placental vascularization and alters its development, ultimately affecting fetal growth
Dr. Jorge López-Tello, a researcher at the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, has participated in a study led by the group of Dr. Vicente Pérez-García at the Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, published in Stem Cell Reports. The study demonstrates that the IRS2 protein (insulin receptor substrate 2) coordinates placental formation by transmitting signals from insulin-like growth factors (IGF1 and IGF2) through the PI3K/AKT and ERK1/2 pathways.
In mice deficient in the Irs2 gene, the team observed defective development of the syncytiotrophoblast (a multinucleated cell layer formed by the fusion of trophoblast cells that lines the placental villi and constitutes an essential component of the maternal-fetal barrier), defects in cell fusion, and reduced placental vascularization, resulting in smaller fetuses compared with the control group.
Stem cells to understand the mechanism
To understand why these alterations occur, the researchers also used trophoblast stem cells, precursor cells from which different placental cell types develop.
Using CRISPR/Cas9 gene-editing technology, the team generated cells in which the Irs2 gene was deleted. These experiments showed that IRS2-deficient cells have a reduced proliferative capacity and, most importantly, difficulties in correctly differentiating into the cells that form the placental layer affected in the mice.
The study also made it possible to identify the molecular mechanism involved. The IRS2 protein transmits signals from IGF growth factors to two important cellular pathways that regulate fundamental processes such as cell proliferation and differentiation.
When IRS2 is absent, these signals are transmitted less effectively, reducing the activation of key regulators involved in syncytiotrophoblast formation. The result is defective differentiation of the cells that must build the placental exchange surface.
“What is interesting about IRS2 is that it receives growth signals and uses them to organize the placenta. Without it, the placenta cannot develop properly, and fetal growth is compromised,” explains López-Tello.
Evidence in the human placenta
To assess whether these findings are relevant to humans, the team analyzed single-cell RNA sequencing data from human embryos and embryonic stem cells, as well as from human placenta at 8 weeks of gestation. In all cases, the IRS2 protein was found to be enriched in the syncytiotrophoblast, an observation that was experimentally confirmed through the differentiation of human trophoblast stem cells and the use of placental organoids.
These results are consistent with previous observations reporting reduced levels of IRS2 and its signaling in placentas from pregnancies affected by fetal growth restriction. The study thus provides a possible mechanistic explanation for this association and opens new avenues for understanding the origin of pregnancy complications related to impaired placental function. “Being able to explain at the molecular level why IRS2 levels are reduced in these placentas opens new avenues for understanding the origin of increasingly prevalent pregnancy complications, such as placental insufficiency or fetal growth restriction, which can have short- and long-term consequences for both the mother and the offspring,” adds López-Tello.
The authors point out that further functional studies will be needed to determine whether IRS2 plays the same role in the human placenta as it does in the mouse model.
Reference: Grinat, J. et al. Insulin receptor substrate 2 regulates placental syncytiotrophoblast differentiation at the maternal-fetal interface. Stem Cell Reports 21, 103061 (2026). https://doi.org/10.1016/j.stemcr.2026.103061